{{short description|Series of interconnected biochemical reactions}}{{cs1 config|name-list-style=vanc|display-authors=6}}

The glycolysis pathway can be separated into two phases:<ref name="glycolysis_animation">{{cite web | vauthors = Mehta S | date = 20 September 2011 | url = http://pharmaxchange.info/press/2011/09/glycolysis-animation-and-notes/ | title = Glycolysis – Animation and Notes | work = PharmaXchange | access-date = 22 September 2011 | archive-date = 25 March 2012 | archive-url = https://web.archive.org/web/20120325151810/http://pharmaxchange.info/press/2011/09/glycolysis-animation-and-notes/ | url-status = dead }}</ref>

<div style="display:flex; flex-flow:row wrap; border:1px solid #a79c83; margin:1em" class="skin-invert-image>

[[File:Glycolysis.svg|thumb|445x445px|class=skin-invert-image|Glycolysis pathway overview.]]

Charges are balanced by the difference between ADP and ATP. In the cellular environment, all three hydroxyl groups of ADP dissociate into −O⁻ and H⁺, giving ADP³⁻, and this ion tends to exist in an ionic bond with Mg²⁺, giving ADPMg⁻. ATP behaves identically except that it has four hydroxyl groups, giving ATPMg²⁻. When these differences along with the true charges on the two phosphate groups are considered together, the net charges of −4 on each side are balanced.{{cn|date=September 2024}}

| [[File:Metabolism of common monosaccharides, and related reactions.png|none|1000px|class=skin-invert-image]]

The pathwaymodern understanding of glycolysisthe aspathway itof is known todayglycolysis took almost 100 years to fully elucidatelearn.<ref name="pmid12722184">{{cite journal | vauthors = Barnett JA | title = A history of research on yeasts 5: the fermentation pathway | journal = Yeast | volume = 20 | issue = 6 | pages = 509–543 | date = April 2003 | pmid = 12722184 | doi = 10.1002/yea.986 | s2cid = 26805351 | doi-access = free }}</ref> The combined results of many smaller experiments were required in order to understand the intricacies of the entire pathway.

The first steps in understanding glycolysis began in the nineteenth19th century with the wine industry. For economic reasons, the French wine industry sought to investigate why wine sometimes turned distasteful, instead of fermenting into alcohol. The French scientist [[Louis Pasteur]] researched this issue during the 1850s, and the results of his experiments began the long road to elucidating the pathway of glycolysis.<ref>{{cite web |title=Louis Pasteur and Alcoholic Fermentation |url=http://www.pasteurbrewing.com/articles/beer-wine-fermentation.html |website=www.pasteurbrewing.com |access-date=2016-02-23 |archive-url=https://web.archive.org/web/20110113030412/http://www.pasteurbrewing.com/articles/beer-wine-fermentation.html |archive-date=2011-01-13 |url-status=dead }}</ref> His experiments showed that alcohol fermentation occurs by the action of living [[microorganism]]s, yeasts, and that yeast's glucose consumption decreased under aerobic conditions of fermentation, in comparison to anaerobic conditions (the [[Pasteur effect]]).<ref>{{cite journal | vauthors = Alba-Lois L, Segal-Kischinevzky C | title = Yeast fermentation and the making of beer and wine. | journal = Nature Education | date = January 2010 | volume = 3 | issue = 9 | pages = 17 | url = http://www.nature.com/scitable/topicpage/yeast-fermentation-and-the-making-of-beer-14372813 }}</ref>

[[File:Eduardbuchner.jpg|left|thumb|Eduard Buchner. Discovereddiscovered cell-free fermentation.]]

Insight into theThe component steps of glycolysis were providedfirst analysed by the non-cellular fermentation experiments of [[Eduard Buchner]] during the 1890s.<ref>{{cite journal | vauthors = Kohler R | title = The background to Eduard Buchner's discovery of cell-free fermentation | journal = Journal of the History of Biology | volume = 4 | issue = 1 | pages = 35–61 | date = 1971-03-01 | pmid = 11609437 | doi = 10.1007/BF00356976 | s2cid = 46573308 }}</ref><ref>{{cite web |title=Eduard Buchner - Biographical |url=https://www.nobelprize.org/nobel_prizes/chemistry/laureates/1907/buchner-bio.html |website=www.nobelprize.org |access-date=2016-02-23}}</ref> Buchner demonstrated that the conversion of glucose to ethanol was possible using a non-living extract of yeast, due to the action of [[enzyme]]s in the extract.<ref name = "Cornish-Bowden_1997">{{cite book |publisher=Publicacions de la Universitat de València |title=New Beer in an Old Bottle: Eduard Buchner and the Growth of Biochemical Knowledge | editor-first = Athel | editor-last = Cornish-Bawden |year=1997 |location=Valencia, Spain |chapter=Harden and Young's Discovery of Fructose 1,6-Bisphosphate}}</ref>{{rp|135–148}} This experiment not only revolutionized biochemistry, but also allowed later scientists to analyze this pathway in a more controlled laboratory setting. In a series of experiments (1905-19111905–1911), scientists [[Arthur Harden]] and [[William John Young (biochemist)|William Young]] discovered more pieces of glycolysis.<ref name=":1">{{Cite book|title=Bios 302| vauthors = Palmer G |url=http://www.bioc.rice.edu/~graham/Bios302/chapters/Chapter_3.pdf | archive-url = https://web.archive.org/web/20171118060851/http://www.bioc.rice.edu/~graham/Bios302/chapters/Chapter_3.pdf | archive-date = 18 November 2017 |chapter=Chapter 3: The History of Glycolysis: An Example of a Linear Metabolic Pathway. }}</ref> They discovered the regulatory effects of ATP on glucose consumption during alcohol fermentation. They also shed light on the role of one compound as a glycolysis intermediate: fructose 1,6-bisphosphate.<ref name = "Cornish-Bowden_1997" />{{rp|151–158}}

[[File:Otto Fritz Meyerhof.jpg|thumb|Otto Meyerhof., Oneone of the main scientists involved in completing the puzzle of glycolysis]]

|minor_forward_substrate(s)=ADP + H⁺

Using the measured concentrations of each step, and the standard free energy changes, the actual free energy change can be calculated. (Neglecting this is very common - thecommon—the delta G of ATP hydrolysis in cells is not the standard free energy change of ATP hydrolysis quoted in textbooks).

! colspan=2|Δ''G''°′ <br> (kJ/mol)

! colspan=2|Δ''G'' <br> (kJ/mol)

| {{decimal cell|−16.7}}

| {{decimal cell|−34}}

| {{decimal cell|1.67}}

| {{decimal cell|−2.9}}

| {{decimal cell|−14.2}}

| {{decimal cell|−19}}

| {{decimal cell|23.9}}

| {{decimal cell|−0.23}}

| {{decimal cell|7.56}}

| {{decimal cell|2.4}}

| {{decimal cell|6.30}}

| {{decimal cell|−1.29}}

| {{decimal cell|−18.9}}

| {{decimal cell|0.09}}

| {{decimal cell|4.4}}

| {{decimal cell|0.83}}

| {{decimal cell|1.8}}

| {{decimal cell|1.1}}

| {{decimal cell|−31.7}}

| {{decimal cell|−23.0}}

From measuring the physiological concentrations of metabolites in an erythrocyte it seems that about seven of the steps in glycolysis are in equilibrium for that cell type. Three of the steps — thesteps—the ones with large negative free energy changes — arechanges—are not in equilibrium and are referred to as ''irreversible''; such steps are often subject to regulation.

[[Glucokinase]], unlike [[hexokinase]], is not inhibited by G6P. It occurs in liver cells, and will only phosphorylate the glucose entering the cell to form [[glucose-6-phosphate]] (G6P), when the glucose in the blood is abundant. This being the first step in the glycolytic pathway in the liver, it therefore imparts an additional layer of control of the glycolytic pathway in this organ.<ref name=stryer />

[[Fructose 2,6-bisphosphate]] (F2,6BP) is a very potent activator of phosphofructokinase (PFK-1) that is synthesized when F6P is phosphorylated by a second phosphofructokinase ([[PFK2]]). In the liver, when blood sugar is low and [[glucagon]] elevates cAMP, [[PFK2]] is phosphorylated by [[protein kinase A]]. The phosphorylation inactivates [[PFK2]], and another domain on this protein becomes active as [[fructose bisphosphatase-2]], which converts F2,6BP back to F6P. Both [[glucagon]] and [[epinephrine]] cause high levels of cAMP in the liver. The result of lower levels of liver fructose-2F2,6-bisphosphate6BP is a decrease in activity of [[phosphofructokinase]] and an increase in activity of [[fructose 1,6-bisphosphatase]], so that gluconeogenesis (in essence, "glycolysis in reverse") is favored. This is consistent with the role of the liver in such situations, since the response of the liver to these hormones is to release glucose to the blood.

[[Adenosine triphosphate|ATP]] competes with [[Adenosine monophosphate|AMP]] for the allosteric effector site on the PFK enzyme. ATP concentrations in cells are much higher than those of AMP, typically 100-fold higher,<ref>{{cite journal | vauthors = Beis I, Newsholme EA | title = The contents of adenine nucleotides, phosphagens and some glycolytic intermediates in resting muscles from vertebrates and invertebrates | journal = The Biochemical Journal | volume = 152 | issue = 1 | pages = 23–32 | date = October 1975 | pmid = 1212224 | pmc = 1172435 | doi = 10.1042/bj1520023 }}</ref> but the concentration of ATP does not change more than about 10% under physiological conditions, whereas a 10% drop in ATP results in a 6-fold increase in AMP.<ref>{{cite book | vauthors = Voet D, Voet JG | date = 2004 | title = Biochemistry | edition = 3rd | location = New York | publisher = John Wiley & Sons, Inc. }}</ref> Thus, the relevance of ATP as an allosteric effector is questionable. An increase in AMP is a consequence of a decrease in [[energy charge]] in the cell.

The final step of glycolysis is catalysed by pyruvate kinase to form pyruvate and another ATP. It is regulated by a range of different transcriptional, covalent and non-covalent regulation mechanisms, which can vary widely in different tissues.<ref>{{cite journal | vauthors = Carbonell J, Felíu JE, Marco R, Sols A | title = Pyruvate kinase. Classes of regulatory isoenzymes in mammalian tissues | journal = European Journal of Biochemistry | volume = 37 | issue = 1 | pages = 148–156 | date = August 1973 | pmid = 4729424 | doi = 10.1111/j.1432-1033.1973.tb02969.x | hdl = 10261/78345 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Valentini G, Chiarelli L, Fortin R, Speranza ML, Galizzi A, Mattevi A | title = The allosteric regulation of pyruvate kinase | journal = The Journal of Biological Chemistry | volume = 275 | issue = 24 | pages = 18145–18152 | date = June 2000 | pmid = 10751408 | doi = 10.1074/jbc.m001870200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Israelsen WJ, Vander Heiden MG | title = Pyruvate kinase: Function, regulation and role in cancer | journal = Seminars in Cell & Developmental Biology | volume = 43 | pages = 43–51 | date = July 2015 | pmid = 26277545 | pmc = 4662905 | doi = 10.1016/j.semcdb.2015.08.004 }}</ref> For example, in the liver, pyruvate kinase is regulated based on glucose availability. During fasting (no glucose available), [[glucagon]] activates [[protein kinase A]] which phosphorylates pyruvate kinase to inhibit it.<ref name=":4">{{cite journal | vauthors = Engström L | title = The regulation of liver pyruvate kinase by phosphorylation--dephosphorylation | journal = Current Topics in Cellular Regulation | volume = 13 | pages = 28–51 | date = 1978 | pmid = 208818 | doi = 10.1016/b978-0-12-152813-3.50006-9 | publisher = Elsevier | isbn = 978-0-12-152813-3 }}</ref> An increase in blood sugar leads to secretion of [[insulin]], which activates [[protein phosphatase 1]], leading to dephosphorylation and re-activation of pyruvate kinase.<ref name=":4" /> These controls prevent pyruvate kinase from being active at the same time as the enzymes that catalyze the reverse reaction ([[pyruvate carboxylase]] and [[phosphoenolpyruvate carboxykinase]]), preventing a [[futile cycle]].<ref name=":4" /> Conversely, the isoform of pyruvate kinasein found in muscle is not affected by [[protein kinase A]] (which is activated by adrenaline in that tissue), so that glycolysis remains active in muscles even during fasting.<ref name=":4" />

[[Lactic acid fermentation]] and [[ethanol fermentation]] can occur in the absence of oxygen. This anaerobic fermentation allows many single-cell organisms to use glycolysis as their only energy source.

* Firstly, the [[Nicotinamide adenine dinucleotide|NADH + H⁺]] generated by glycolysis has to be transferred to the mitochondrion to be oxidized, and thus to regenerate the NAD⁺ necessary for glycolysis to continue. However the inner mitochondrial membrane is impermeable to NADH and NAD⁺.<ref name=stryer5>{{cite book | vauthors = Stryer L | title = Biochemistry |chapter= Oxidative phosphorylation. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 537–549 |isbn= 0-7167-2009-4 }}</ref> Use is therefore made of two “shuttles”"shuttles" to transport the electrons from NADH across the mitochondrial membrane. They are the [[malate-aspartate shuttle]] and the [[glycerol phosphate shuttle]]. In the former the electrons from NADH are transferred to cytosolic [[Oxaloacetic acid|oxaloacetate]] to form [[Malic acid|malate]]. The malate then traverses the inner mitochondrial membrane into the mitochondrial matrix, where it is reoxidized by NAD⁺ forming intra-mitochondrial oxaloacetate and NADH. The oxaloacetate is then re-cycled to the cytosol via its conversion to aspartate which is readily transported out of the mitochondrion. In the glycerol phosphate shuttle electrons from cytosolic NADH are transferred to [[dihydroxyacetone]] to form [[glycerol-3-phosphate]] which readily traverses the outer mitochondrial membrane. Glycerol-3-phosphate is then reoxidized to dihydroxyacetone, donating its electrons to [[Flavin adenine dinucleotide|FAD]] instead of NAD⁺.<ref name=stryer5 /> This reaction takes place on the inner mitochondrial membrane, allowing FADH₂ to donate its electrons directly to coenzyme Q ([[ubiquinone]]) which is part of the [[electron transport chain]] which ultimately transfers electrons to molecular oxygen {{chem2|O2}}, with the formation of water, and the release of energy eventually captured in the form of [[Adenosine triphosphate|ATP]].

[[Nicotinamide adenine dinucleotide|NAD⁺]] is the oxidizing agent in glycolysis, as it is in most other energy yielding metabolic reactions (e.g. [[beta-oxidation]] of fatty acids, and during the [[citric acid cycle]]). The NADH thus produced is primarily used to ultimately transfer electrons to {{chem2|O2}} to produce water, or, when {{chem2|O2}} is not available, to produce compounds such as [[Lactic acid|lactate]] or [[ethanol]] (see ''Anoxic regeneration of NAD⁺'' above). NADH is rarely used for synthetic processes, the notable exception being [[gluconeogenesis]]. During [[Fatty acid metabolism#Fatty acid Synthesis|fatty acid]] and [[Cholesterol#Biosyntesis|cholesterol synthesis]] the reducing agent is [[Nicotinamide adenine dinucleotide phosphate|NADPH]]. This difference exemplifies a general principle that NADPH is consumed during biosynthetic reactions, whereas NADH is generated in energy-yielding reactions.<ref name=stryer0 /> The source of the NADPH is two-fold. When [[Malic acid|malate]] is oxidatively decarboxylated by “NADP"NADP⁺-linked malic enzyme" [[Pyruvic acid|pyruvate]], {{chem2|CO2}} and NADPH are formed. NADPH is also formed by the [[pentose phosphate pathway]] which converts glucose into ribose, which can be used in synthesis of [[nucleotides]] and [[nucleic acids]], or it can be catabolized to pyruvate.<ref name=stryer0 />

Cellular uptake of glucose occurs in response to insulin signals, and glucose is subsequently broken down through glycolysis, lowering blood sugar levels. However, theinsulin resistance or low insulin levels seen in diabetes result in hyperglycemia, where glucose levels in the blood rise and glucose is not properly taken up by cells. Hepatocytes further contribute to this hyperglycemia through [[gluconeogenesis]]. Glycolysis in hepatocytes controls hepatic glucose production, and when glucose is overproduced by the liver without having a means of being broken down by the body, hyperglycemia results.<ref>{{Cite journal|date=2012-08-01|title=Glycolysis in the control of blood glucose homeostasis|journal=Acta Pharmaceutica Sinica B|language=en|volume=2|issue=4|pages=358–367|doi=10.1016/j.apsb.2012.06.002|issn=2211-3835| vauthors = Guo X, Li H, Xu H, Woo S, Dong H, Lu F, Lange AJ, Wu C |doi-access=free}}</ref>

This high glycolysis rate has important medical applications, as high [[Aerobic_fermentationAerobic fermentation| aerobic glycolysis]] by malignant tumors is utilized clinically to diagnose and monitor treatment responses of [[cancer]]s by [[Chemical imaging|imaging]] uptake of [[Fluorodeoxyglucose|2-¹⁸F-2-deoxyglucose]] (FDG) (a [[radioactive]] modified hexokinase [[substrate (biochemistry)|substrate]]) with [[positron emission tomography]] (PET).<ref name="pmid11043392">{{cite journal | vauthors = Pauwels EK, Sturm EJ, Bombardieri E, Cleton FJ, Stokkel MP | title = Positron-emission tomography with [18F]fluorodeoxyglucose. Part I. Biochemical uptake mechanism and its implication for clinical studies | journal = Journal of Cancer Research and Clinical Oncology | volume = 126 | issue = 10 | pages = 549–59 | date = October 2000 | pmid = 11043392 | doi = 10.1007/pl00008465 | s2cid = 2725555 }}</ref><ref>{{cite web | title=PET Scan: PET Scan Info Reveals ... | url=http://www.petscaninfo.com/ | access-date=December 5, 2005 }}</ref>

The intermediates of glycolysis depicted in Fischer projections show the chemical changing step by step. Such image can be compared to polygonal model representation.<ref name="bonafe">{{cite journal | vauthors = Bonafe CF, Bispo JA, de Jesus MB | title = The polygonal model: A simple representation of biomolecules as a tool for teaching metabolism | journal = Biochemistry and Molecular Biology Education | volume = 46 | issue = 1 | pages = 66–75 | date = January 2018 | pmid = 29131491 | doi = 10.1002/bmb.21093 | s2cid = 31317102 | doi-access = free }}</ref> Another comparation of Fischer projections and Poligonal Model in glycolysis is shown in a video.<ref>{{cite web| vauthors = Bonafe C |url=https://www.youtube.com/watch?v=PaX9NOb8oX4&list=UUF-2nRkGkKY-O-st3tMzQ8Q&index=19.htm| archive-url=https://ghostarchive.org/varchive/youtube/20211104/PaX9NOb8oX4| archive-date=2021-11-04 | url-status=live|title=Introduction to Polygonal Model - PART 1. Glycolysis and Structure of the Participant Molecules.|date=23 September 2019|work=YouTube}}{{cbignore}}</ref> Video animations in the same channel in YouTube can be seen for another metabolic pathway (Krebs Cycle) and the representation and applying of Polygonal Model in Organic Chemistry <ref>{{cite web|title=Metabolism Animation and Polygonal Model|url=https://www.youtube.com/channel/UCF-2nRkGkKY-O-st3tMzQ8Q?view_as=subscriber|work=YouTube|access-date=2019-12-11|language=en}}</ref>

[[Category:BiochemistryBiochemical reactions]]